Synthesis of thyrotropin-releasing hormone analogues with selective central nervous system effects.
Thyrotropin-releasing hormone (TRH) analogues which show relative selectivity for action in the central nervous system have been recognized. Practical syntheses for three of these TRH analogues which show the greatest selectivity, less than Aad-His-Tzl-NH2 (5), less than Glu-His-Pip-OMe (2), and less than Aad-His-Pro-NH2 (6), are described. The first two were prepared by solution methods of peptide synthesis. Compound 6 was prepared by the solid-phase method. Problems of histidine racemization, facile diketopiperazine formation, and instability of acylated thiazolidine carboxylic acid derivatives under acidic conditions have been minimized in order to attain optimal yields. Physical properties such as pK, NMR shifts, and circular dichroism have been examined as they might relate to biological activity and peptide conformation.
D002490:Central Nervous System / Q000187:drug effects*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D053778:Thiazolidines; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism
D053778:Thiazolidines; D014284:Triiodothyronine; C031092:pyro(alpha-aminoadipyl)-histidyl-prolinamide; D013973:Thyrotropin-Releasing Hormone; C031093:methyl pyroglutamyl-histidyl-pipecolate; C021597:pyro(l-alpha-aminoadipyl)-L-histidyl-L-thiazolidine-4-carboxamide; D013974:Thyroxine; D011761:Pyrrolidonecarboxylic Acid